1. Field of the Invention
The invention relates to supplements containing sialic acid and the use of such supplements for a female that can result in developmental benefits for a fetus and/or child.
2. Background Art
The rapid growth and development of a fetus or child places significant demand on the maternal supply of nutrients. See, e.g., Crawford et al., Eur. J. Pediatr. 1998; 157:23-27. Nutrient deficits have profound effects on the growth and structural/functional development of the fetus or child, particularly in the growth and development of the brain. Brain growth, including cell number and structural and synaptic connectivity, reaches its peak at 26 weeks of gestation and continues at a high rate throughout the first year of life. This period of brain growth is critical because once the period has passed, it cannot be restarted. Furthermore, this period of growth is particularly important in premature infants. See, e.g., Crawford et al., Eur. J. Pediatr. 1998; 157:23-27.
Numerous studies indicate that breast-fed infants achieve better cognitive development and attain higher scores on intelligence tests than bottle-fed babies. See, e.g., Mortensen et al., JAMA 2002; 287:2365-2371. For example, intelligence quotient (IQ) has been shown to increase in infants receiving a longer duration of breastfeeding, particularly in low birth weight infants. See, e.g., Anderson et al., Am. J. Clin. Nutr. 1999; 70:525-535.
Complex lipids from gangliosides, as well as long-chain polyunsaturated fatty acids (LCPUFAs) such as docosahexaenoic acid (DHA), are present in human milk and have been implicated in the improvement of visual acuity and cognitive ability in children. See, e.g., International Publication No. WO 2009/051502 A1 and Gibson, Lancet 1999; 354:1919-1920. However, other components of human milk might be important to brain growth and development of a fetus or child. These factors, such as enzymes, hormones, growth factors, and sialic acid, are found in human milk and are typically poorly represented in infant formulas. See, e.g., McVeagh and Miller, J. Paediatr. Child Health 1997; 33:281-286.
Of the factors described above, sialic acid has been shown to have a simultaneous presence in significant amounts in both human milk and human brain. See, e.g., McVeagh and Miller, J. Paediatr. Child Health 1997; 33:281-286. Sialic acid is a generic term for the N- or O-substituted derivatives of neuraminic acid, a monosaccharide with a nine-carbon backbone, that are a structural and functional component of gangliosides. See, e.g., Varki and Schauer (2009) in Essentials of Glycobiology. 2nd ed., Cold Spring Harbor Press. Ch. 14; and FIG. 1. The most predominant sialic acid found in mammals is N-acetylneuraminic acid (NANA).
Certain roles for sialic acid in development and disease pathology have been described. For example, inactivation of the gene encoding an enzyme of sialic acid biosynthesis, uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) 2-epimerase/N-acetylmannosamine (MacNAc) kinase (GNE/MNK), has been correlated with reduced sialic acid levels and the development of hereditary inclusion body myopathy (HIBM), an adult-onset progressive neuromuscular disorder. See, e.g., Galeano et al., J. Clin. Invest. 2007; 117:1585-1594; Malicdan et al., Nature Med. 2009; 15:690-695; and Huizing and Krasnewich, Biochim. Biophys. Acta 2009; 1792:881-887. Also, inactivation of the UDP-GlcNAc/MacNAc gene has been described to result in early embryonic lethality in mice, suggesting a role for the UDP-GlcNAc/MacNAc gene in development. See, e.g., Schwarzkopf et al., PNAS 2002; 99:5267-5270. The use of sialic acid to support the immune system and re-establish central and peripheral nervous system health in the elderly has also been described. See, e.g., European Patent Application Nos. 2116140 A1 and 2116139 A1.
A mother's increased intake of some nutrients (e.g., docosahexaenoic acid) can benefit her child's brain development. However, there has been no evidence that the quantity of sialic acid a mother naturally makes is inadequate. As shown in the Examples, maternal supplementation with sialic acid clearly resulted in developmental benefits for a fetus or child, suggesting that maternal supplementation with sialic acid is needed. The present invention addresses this need by providing sialic acid which can be administered to a female during preconception, pregnancy/gestation and/or lactation/postpartum as described herein.
While maternal supplementation with NANA has not been previously described, Hedlund et al. (Mol. Cell. Biol. 2007; 27:4340-4346) reported feeding another sialic acid, N-glycolylneuraminic acid (Neu5Gc), to mice lacking the gene to produce Neu5Gc. The researchers reported that feeding Neu5Gc to dams lacking this gene does not transfer Neu5Gc to pups that also lack the gene. In addition, adult mammals are known to readily synthesize sufficient levels of sialic acid and there is no clear evidence regarding whether or not the mother supplies sialic acid to the fetus through the maternoplacental unit. See, e.g., Briese et al., Z. Geburtsh. Neonatol. 1999; 203:63-68.
The most rapid rate of brain development (“the brain growth spurt”) occurs during gestation and extends to at least the end of the first year of life. As such, the present invention optimizes the developmental benefits of maternal supplements such as sialic acid for a fetus or child by providing supplementation during this critical period of brain development.